Antibody drug conjugates (ADCs) deliver therapeutic molecules preferentially to cancer cells compared to normal tissue. Unfortunately, ADCs penetrate poorly into most solid tumors and fail to cross the blood brain barrier, limiting utilityfor pressing needs in oncology. Our lab invented Tumor Paint, a peptide drug conjugate (PDC) that crosses the blood brain barrier and penetrates throughout brain tumors and other solid tumors. Tumor Paint, which is on track to enter clinical trials in late 2013, preferentially delivers indocyanine green (ICG) to cancer cells using a variant of CTX, a scorpion-derived knotted peptide as the targeting agent. Upon binding to cell surface Annexin II (Annexin A2) on cancer cells, CTX conjugates are rapidly internalized, which is ideal for imaging and also ideal for therapeutic delivery. Toward the goal of using knotted peptides (knottins) to deliver therapeutics to cancer cells, our team developed a platform that enables production of 10,000 peptide drug candidates in 3 weeks. We identified and overcame other major barriers to developing knotted peptides as targeting agents for cancer. We hypothesize that knottin peptides can be engineered to specifically and effectively deliver therapeutics to solid tumors. Our Aims are to (1) Develop a clinical lead peptide-drug conjugate that preferentially delivers a radiosensitizer t brain tumors and (2) Identify a peptide drug conjugate that preferentially induces cell death in brain tumors. The significance of this work is that it creates a potentially superior alternative t ADCs for effective and safe delivery of therapeutics directly to brain tumors.